PROJECT SUMMARY Breast cancer risk in foreign-born Latinas is approximately half of that in U.S.-born Latinas, and increases with longer U.S. residency. It is only partially known what factors contribute to these risk patterns. We propose a multidisciplinary, cells-to-society approach that shifts paradigms from a targeted breast cancer candidate exposure analysis to a broad exploratory study of the myriad exposures reflected in an individual?s internal chemical environment. We will combine this approach with small area-level contextual measures of socioeconomic and built environments (e.g., ethnic enclaves, urbanity, traffic density), and data on individual behaviors and demographic information, with the long term objective of discovering specific chemicals or compounds, of endogenous or exogenous origin, that lead to the increase in breast cancer risk among U.S.- born Latinas. As part of this specific proposal we plan to use mass-spectrometry (a substance separation procedure) and cell-based assays to measure two types of harmful substances: reactive electrophiles (substances attracted to electrons that damage DNA and proteins) and hormone receptor disruptors (chemicals that mimic the effect of hormones on cell receptors). We will evaluate the levels of these molecules in 285 postmenopausal Latina women who participated in the San Francisco Bay Area Breast Cancer Study (SFBCS), a population-based case-control study of women aged 35 to 79 years. Of the 285 women, 189 are foreign-born and 96 U.S.-born. Additionally, we will compare the levels of reactive electrophiles in 146 Latina women who have been diagnosed with postmenopausal breast cancer to those of the healthy controls. Based on preliminary data, we hypothesize that foreign-born Latinas of relatively high Indigenous American ancestry are exposed to lower levels of endocrine disruptors and reactive electrophiles than U.S.-born Latinas, which contributes to their lower risk of breast cancer. In addition, we hypothesize that neighborhood characteristics, such as urbanity, might be associated with levels of exposure to these carcinogenic compounds. Specific aims 1 and 2 of the proposal will test the association between estrogenic, glucocorticogenic and reactive electrophile levels and Indigenous American ancestry in U.S. Latinas by nativity, and explore their relationship with spatially defined neighborhood characteristics. The third aim of the study will test the difference in levels of specific reactive electrophiles between breast cancer cases and controls. We expect that the present study will lead to the discovery of reactive molecules that might contribute to observed differences in breast cancer risk between U.S.-born and foreign-born Latinas, and to the understanding of their variation between different neighborhood contexts. In addition, the proposed research will provide novel avenues of inquiry regarding the specific compounds that activate or block hormone receptors and that might contribute to breast cancer risk. This knowledge will be crucial to develop prevention and regulatory programs aimed at reducing breast cancer incidence not only in U.S.-born Latinas, but in all women.